This study proposes to use the large registries of colorectal cancer (CRC) families accumulated by the John Hopkins University (JHU) and University of Utah research groups to systematically evaluate the phenotypic and genetic heterogeneity of hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP), and multiplex colorectal cancer kindreds. These studies are crucial to our understanding of gene-environment interactions in colon cancer etiology. Our aims are outlined below. Using our combined CRC (hereditary and sporadic) registry resources we propose to: 1. Evaluate the rate of occurrence of the newly-described replication error (RER) molecular phenotype in CRCs of 200 incident sporadic CRC patients seen at JHU, 50 patients (JHU and Utah) from unrelated families which fulfill diagnostic criteria of HNPCC, and 50 patients (JHU and Utah) from unrelated multiplex CRC kindreds which do not meet the criteria for HNPCC. 2. Test for differences between RER phenotype and clinical/epidemiologic data on the patients tested in Specific Aim 1. These data include age at diagnosis, cancer site, multiplicity of cancers in the patient, family history of CRC, and p53, DCC, and RAS gene changes in the CRCs. 3. Determine concordance of RER phenotype in CRCs of relatives from multiplex families and 20 CRC kindreds). This analysis will stratify the families based on evidence of linkage or non-linkage to chromosome 2. Using the John Hopkins FAP registry resource, we propose to: 4. Characterize mutations in the FAP-causing gene (APC) in 250 unrelated FAP patients, and test for differences between mutations in different APC domains and clinical/epidemiologic data (age at onset, presence of extracolonic tumors, number of polyps, etc.). 5. Compare clinical/epidemiologic characteristics of affected individuals in FAP families that are and are not linked to the APC gene. 6. Test for the effect of dietary factors on the age of onset of colonic polyps in a cohort of 100 at-risk individuals known by genetic testing to have inherited mutant APC genes. To achieve these aims, concurrently submitted proposals will perform linkage studies (M. Skolnick, PI) and P53 and RAS gene studies (S. Hamilton, PI).